CHKA knockout impairs dendritic development and Wnt pathway regulation in neurodevelopment

Variants in the CHKA gene, encoding choline kinase alpha (CHKA), are associated with epilepsy, intellectual disability, and movement disorders. The neurobiological mechanisms remain unclear. This study examined neuronal subcellular structural changes and molecular pathways in CHKA deficiency.

A CRISPR-Cas9-generated CHKA knockout mouse model was established. Neuronal dendritic architecture and presynaptic vesicle ultrastructure were examined in knockout and control groups using Golgi staining and electron microscopy. Transcriptomic and proteomic analyses were performed to identify pathways and regulatory factors implicated in neurodevelopment and immune microenvironment modulation.

Golgi staining demonstrated that CHKA deficiency was associated with reduced dendritic branching complexity and decreased synaptic connection density in cortical neurons. Electron microscopy revealed a significant increase in total vesicle number within presynaptic terminals in knockout mice, accompanied by a marked reduction in vesicles at fusion docking states. Transcriptomic and proteomic analyses identified pathways and factors potentially associated with neural development.

CHKA deficiency impaired cortical dendritic development and synaptic vesicle maturation in mice. Transcriptomic and proteomic findings implicated neurodevelopmental pathways, with Wnt signaling contributions. These provided mechanistic insights into neurodevelopmental abnormalities in clinical CHKA variants phenotypes.